DESCRIPTION (provided by investigator): Smallpox virus (variola) is a potential biological weapons agent due to its ease of dissemination, person to- person transmissibility and potential to cause widespread illness and death. Smallpox virus is classified as a Category A bioweapons agent by the Centers for Disease Control and Prevention (CDC). Currently, there are no FDA-approved antiviral drugs to prevent or treat smallpox infection. The overall goal of our Smallpox Virus Biodefense Program is to discover and develop small molecule drugs for prevention and treatment of smallpox virus infection. The specific aims of this Phase 1 application are to: 1. Establish a validated virus-specific high throughput-screening assay using a cowpox virus (BSL-2) surrogate for authentic variola virus. 2. Identify specific inhibitors that target wild type and drug resistant variants of cowpox virus from VIROPHARMA's proprietary chemically diverse library of over 400,000 small molecule compounds. 3. Characterize inhibitor compounds ("hits") for chemical tractability, antiviral potency and spectrum and selectivity in order to identify promising "quality hits". 4. Confirm antiviral specificity and selectivity of quality hits against the authentic variola virus in cell culture (performed through collaborating laboratories); 5. Investigate the mechanism of antiviral action of "confirmed quality hits"; and 6. Conduct initial drug metabolism, genotoxicity & pharmacokinetic evaluations on confirmed quality hits. The end result of Phase 1 work will be identification of quality hits specific for variola virus. Advancement of these compounds in Phase 2 will involve: (1) hit-to-lead medicinal chemistry to identify leads with good potential for chemical structure-biological activity relationships (SAR); (2) lead compound optimization for antiviral potency, selectivity and spectrum of antiviral activity and drug metabolic and pharmacokinetics properties; (3) mechanism of action and drug resistance characterizations; and (4) efficacy evaluations in suitable animal models. At the end of Phase 2, we anticipate to have identified at least one pre-clinical candidate compound that is suitable for advancement into formal IND toxicological and model animal efficacy evaluations for the prevention and treatment of smallpox virus infection.